Various disorders, including inherited von Hippel-Lindau (VHL) disease, are associated with elevated expression of HIF-2α. Inherited VHL disease is a cancer syndrome caused by germ line mutations of the VHL tumor suppressor gene. VHL is characterized by angiomas and hemangioblastomas of the brain, spinal cord, and retina. These can lead to cysts and/or tumors of the kidney, pancreas, and adrenal glands (e.g., pheochromocytoma and endolymphatic sac tumors). Renal clear cell carcinoma (RCC) develops in approximately 75% of VHL patients by age 60 and is a leading cause of death in this population. Biallelic loss of VHL gene function is also associated with greater than 60% of all RCC (including sporadic cases). Maranchie et al., Cancer Res., 15: 9190-93 (2005). Thus, subjects with compromised VHL function represent a significant population that has or is at risk for developing cancer, including RCC.
RCC is the most common type of kidney cancer. It is highly resistant to chemotherapy, and the primary treatment for RCC depends largely on surgical removal of cancerous tissue. One current treatment regimen for advanced RCC includes immunotheraphy with interleukin-2 (IL-2), although an IL-2 response is seen in less than 20% of patients with advanced RCC. Sabatino et al., J. Clin. Oncol., 27: 2645-52 (2009); Kirkwood et al., J. Clin. Oncol., 27: 2583-2585 (2009). Additional therapeutic agents for advanced RCC include sorafenib, sunitinib maleate, temsirolimus, and everolimus, though there are few complete responses to these agents in patients with advanced RCC. Many RCC patients are asymptomatic and therefore their RCC can go undetected, for example, until revealed by an unrelated imaging procedure. The median survival rate for untreated, metastatic RCC is 12 months, and the 5-year survival rate is less than 10%. Cho et al., Yonsei Med. J., 49: 451-458 (2008).
There is a desire for new molecular therapies that can be used with diseases associated with increased expression of HIF-2α, including VHL disease and sporadic RCC.